We tested the influence of L-propionylcarnitine (LPC) in modifying mechanical stunning during reflow. Nineteen adolescent anesthetized swine were extracorporeally perfused at control coronary flows for 20 min, supplemented with excess fatty acids (average values 1.1 +/- 0.1 mumol/ml), and subjected to 45 min regional ischemia (-60 delta % decrease in anterior descending flow) followed by 35 min reperfusion. Responses in 10 placebo hearts were compared with those obtained from 9 animals treated with 50 mg/kg LPC at 0 min perfusion and 40 mg/kg at 40 min perfusion. Ischemia in placebo hearts caused a 62.6 delta % decrease in active shortening in anterior descending bed, which failed to recover (-41.4 delta % from control values) during reflow. Conversely, in LPC-treated hearts, decreases in active shortening (-38.6 and -11.6 delta %) during ischemia and reflow, respectively, were significantly smaller (P less than or equal to 0.05). This improved motion was associated with greater rates of myocardial oxygen consumption but similar levels of fatty acid oxidation and fatty acid intermediates. Thus LPC significantly reversed mechanical stunning in myocardial ischemia/reperfusion protocols, presumably because of its positive inotropic properties. This derivative, otherwise innocuous in nature, could represent an attractive new treatment choice for future clinical use.